The interplay between protein phosphorylation and ubiquitylation in regulating the signalling networks of the innate immune system

The innate immune system is vital for defence against infection by microbial pathogens, such as bacteria and viruses, but if this system is deregulated, or fails to stop inflammation once it has done its job, it can cause a variety of inflammatory and autoimmune diseases. These include arthritis, asthma, colitis, lupus, psoriasis and sepsis, type 2 diabetes and even cancers of the blood, such as lymphomas. An understanding of how the immune system is switched on and switched off is therefore vital if we are going to be able to develop improved drugs for the treatment of these diseases that affect millions of individuals worldwide.
My laboratory employs state-of-the-art technologies to study this problem and, over the past two years, three Ph.D. students working under my supervision with MRC support have made important discoveries that have identified novel components of the system and shown for the first time how they can be targeted to treat several conditions, including a type of blood cancer, called DLBCL, as well as the lethal effects of flu as well as
sepsis.

The innate immune system is vital for defence against infection by microbial pathogens, such as bacteria and viruses, but the overproduction of inflammatory mediators, or the failure to resolve inflammation once it has served its purpose, causes many inflammatory and autoimmune diseases. They include arthritis, asthma, colitis, lupus, psoriasis and sepsis and even blood cancers, such as lymphomas. An understanding of the signalling networks that control the production of inflammatory mediators at a molecular level is therefore critical to identify key targets for the development of drugs to boost resistance to infection or to suppress inflammatory and autoimmune diseases.
Protein phosphorylation and ubiquitylation are the two key post-translational modifications that are deployed to regulate the innate immune system. The MRC supported research in my laboratory is focused on understanding how the key transcription factor NF-?B and Interferon Regulatory Factors (IRFs) are switched on to control the production of pro-inflammatory cytokines and interferon ??(IFN?). Over the past two years significant advances in understanding how NF-?B and the IRFs are regulated have been made by the three Ph.D. students in my lab, who are supported by MRC Unit funding. My student Sam Strickson has made important contributions towards the discovery that a hybrid ubiquitin chain, comprising both Lys63-linked and Met1-linked ubiquitin oligomers, is critical to switch on the I?B kinases (IKKs) that activate NF-?B and that the formation of Lys63-linked ubiquitin chains is a prerequisite for the formation of Met1-linked ubiquitin chains. Sam discovered that the anti-inflammatory drug BAY 11-7082 blocks the activation of the IKKs by inactivating the E2 conjugating enzymes required for the formation of Lys63-linked and Met1-linked ubiquitin oligomers. Excitingly, he also found that this drug is effective in destroying cancerous cells from patients with Diffuse Large B-Cell Lymphoma, one of the least treatable forms of this blood cancer. My student Jiang Zhang has discovered that the activation of the IKKs requires two different protein kinases that phosphorylate distinct serine residues in the “activation loops” of the IKKs, a control mechanism that may be of general significance. Another student Nazma Malik has made the unexpected discovery that a drug developed as an inhibitor of the protein kinase PLK1 for the treatment of cancer, blocks the production of IFN? during viral infection by a novel mechanism that is independent of PLK1 and which prevents the recruitment of RNA polymerase II to the IFN? gene promoter. This drug and other molecules with a similar mechanism of action may have therapeutic potential for treating the lethal effects or flu and/or sepsis in which the over-production of IFN? is a major contributory factor.